Project Summary Neuropsychiatric illnesses represent a wide range of complex emotional and behavioral disorders, but many of these are associated with maladaptive social responses. Unfortunately, we do not have a clear enough understanding of the neural mechanisms underlying these disorders or the fundamental symptoms they share. While it has become clear that there is a substantial overlap in the neural circuitry (i.e., the Social Behavior Neural Network) controlling different social and emotional behaviors, the technology to study how behavior emerges from such a complex interacting neural network has been lacking. Variation in social behavior, both across species and within individuals of given species, arises at least in part from genetic and epigenetic differences within the Social Behavior Neural Network, and we are now in a position to understand the molecular mechanisms mediating this variation. These genetic differences are expressed as variations in critical molecular elements of neural circuits such as neurotransmitters, receptors, transporters, growth factors, etc. A significant current limitation to progress in this area is that there are no well-established genome- engineering technologies for some of the best animal species for studying social behavior and organization. Among these organisms are Syrian hamsters (Mesocricetus auratus), which have proven to be an exceptionally useful rodent model for the study of social behavior and for which there is a wealth of data, much of which has been generated by the PIs, on the neurobiological and hormonal mechanisms controlling social recognition, social avoidance, aggression, and social communication. The goal of this project is to overcome this limitation by developing and implementing state of the art genome engineering technologies in the Syrian hamster model to enable molecular interrogation of how genes act within neural circuits to regulate complex social behavior. To achieve this goal, we will use genome engineering to generate transgenic and gene- targeted mutant hamsters that will be used to investigate the function of genes that have been implicated in social behavior. The generation of these transgenic and gene-targeted hamsters will be facilitated by our recently generated Syrian hamster transcriptome data, which will be used to specifically target and manipulate a variety of neurobehaviorally-relevant hamster genes. Initially, as a proof of principle, we will focus on the arginine-vasopressin V1a receptor because of the significance of this receptor in regulating a wide range of distinct social behaviors and our long-demonstrated expertise with studying this system. The successful development of transgenic and gene-targeting approaches for Syrian hamsters will provide transformative tools to the research community for exploring the neurogenetic bases of social behaviors.